Receptor (biochemistry)

Ligands connect to specific receptor proteins based on de shape of de active site of de protein, uh-hah-hah-hah.

The receptor reweases a messenger once de wigand has connected to de receptor.

In biochemistry and pharmacowogy, a receptor is a proteinmowecuwe dat receives chemicaw signaws from outside a ceww.[1] When such chemicaw signaws bind to a receptor, dey cause some form of cewwuwar/tissue response, e.g. a change in de ewectricaw activity of a ceww. There are dree main ways de action of de receptor can be cwassified: reway of signaw, ampwification, or integration, uh-hah-hah-hah.[2] Rewaying sends de signaw onward, ampwification increases de effect of a singwe wigand, and integration awwows de signaw to be incorporated into anoder biochemicaw padway.[2] In dis sense, a receptor is a protein-mowecuwe dat recognizes and responds to endogenous chemicaw signaws, e.g. an acetywchowine receptor recognizes and responds to its endogenous wigand, acetywchowine. However, sometimes in pharmacowogy, de term is awso used to incwude oder proteins dat are drug targets, such as enzymes, transporters, and ion channews.

Each receptor is winked to a specific cewwuwar biochemicaw padway. Whiwe numerous receptors are found in most cewws, each receptor wiww onwy bind wif wigands of a particuwar structure, much wike how wocks wiww onwy accept specificawwy shaped keys. When a wigand binds to its corresponding receptor, it activates or inhibits de receptor's associated biochemicaw padway.

The structures of receptors are very diverse and incwude de fowwowing major categories, among oders:

Type 1: Ligand-gated ion channews (ionotropic receptors) – These receptors are typicawwy de targets of fast neurotransmitters such as acetywchowine (nicotinic) and GABA; and, activation of dese receptors resuwts in changes in ion movement across a membrane. They have a heteromeric structure in dat each subunit consists of de extracewwuwar wigand-binding domain and a transmembrane domain where de transmembrane domain in turn incwudes four transmembrane awpha hewices. The wigand-binding cavities are wocated at de interface between de subunits.

Type 2: G protein-coupwed receptors (metabotropic receptors) – This is de wargest famiwy of receptors and incwudes de receptors for severaw hormones and swow transmitters e.g. dopamine, metabotropic gwutamate. They are composed of seven transmembrane awpha hewices. The woops connecting de awpha hewices form extracewwuwar and intracewwuwar domains. The binding-site for warger peptide wigands is usuawwy wocated in de extracewwuwar domain whereas de binding site for smawwer non-peptide wigands is often wocated between de seven awpha hewices and one extracewwuwar woop.[3] The aforementioned receptors are coupwed to different intracewwuwar effector systems via G proteins.[4]

Type 3: Kinase-winked and rewated receptors (see "Receptor tyrosine kinase" and "Enzyme-winked receptor") – They are composed of an extracewwuwar domain containing de wigand binding site and an intracewwuwar domain, often wif enzymatic-function, winked by a singwe transmembrane awpha hewix. The insuwin receptor is an exampwe.

Type 4: Nucwear receptors – Whiwe dey are cawwed nucwear receptors, dey are actuawwy wocated in de cytopwasm and migrate to de nucweus after binding wif deir wigands. They are composed of a C-terminaw wigand-binding region, a core DNA-binding domain (DBD) and an N-terminaw domain dat contains de AF1(activation function 1) region, uh-hah-hah-hah. The core region has two zinc fingers dat are responsibwe for recognizing de DNA seqwences specific to dis receptor. The N terminus interacts wif oder cewwuwar transcription factors in a wigand-independent manner; and, depending on dese interactions, it can modify de binding/activity of de receptor. Steroid and dyroid-hormone receptors are exampwes of such receptors.[5]

One measure of how weww a mowecuwe fits a receptor is its binding affinity, which is inversewy rewated to de dissociation constantKd. A good fit corresponds wif high affinity and wow Kd. The finaw biowogicaw response (e.g. second messenger cascade, muscwe-contraction), is onwy achieved after a significant number of receptors are activated.

Affinity is a measure of de tendency of a wigand to bind to its receptor. Efficacy is de measure of de bound wigand to activate its receptor.

Not every wigand dat binds to a receptor awso activates dat receptor. The fowwowing cwasses of wigands exist:

(Fuww) agonists are abwe to activate de receptor and resuwt in a strong biowogicaw response. The naturaw endogenous wigand wif de greatest efficacy for a given receptor is by definition a fuww agonist (100% efficacy).

Antagonists bind to receptors but do not activate dem. This resuwts in a receptor bwockade, inhibiting de binding of agonists and inverse agonists. Receptor antagonists can be competitive (or reversibwe), and compete wif de agonist for de receptor, or dey can be irreversibwe antagonists dat form covawent bonds (or extremewy high affinity non-covawent bonds) wif de receptor and compwetewy bwock it. The proton pump inhibitor omeprazowe is an exampwe of an irreversibwe antagonist. The effects of irreversibwe antagonism can onwy be reversed by syndesis of new receptors.

Awwosteric moduwators: They do not bind to de agonist-binding site of de receptor but instead on specific awwosteric binding sites, drough which dey modify de effect of de agonist. For exampwe, benzodiazepines (BZDs) bind to de BZD site on de GABAA receptor and potentiate de effect of endogenous GABA.

Note dat de idea of receptor agonism and antagonism onwy refers to de interaction between receptors and wigands and not to deir biowogicaw effects.

A receptor which is capabwe of producing a biowogicaw response in de absence of a bound wigand is said to dispway "constitutive activity".[6] The constitutive activity of a receptor may be bwocked by an inverse agonist. The anti-obesity drugs rimonabant and taranabant are inverse agonists at de cannabinoid CB1 receptor and dough dey produced significant weight woss, bof were widdrawn owing to a high incidence of depression and anxiety, which are bewieved to rewate to de inhibition of de constitutive activity of de cannabinoid receptor.

Mutations in receptors dat resuwt in increased constitutive activity underwie some inherited diseases, such as precocious puberty (due to mutations in wuteinizing hormone receptors) and hyperdyroidism (due to mutations in dyroid-stimuwating hormone receptors).

The centraw dogma of receptor pharmacowogy is dat a drug effect is directwy proportionaw to de number of receptors dat are occupied. Furdermore, a drug effect ceases as a drug-receptor compwex dissociates.

In contrast to de accepted Occupation Theory, Rate Theory proposes dat de activation of receptors is directwy proportionaw to de totaw number of encounters of a drug wif its receptors per unit time. Pharmacowogicaw activity is directwy proportionaw to de rates of dissociation and association, not de number of receptors occupied:[9]

Agonist: A drug wif a fast association and a fast dissociation, uh-hah-hah-hah.

Partiaw-agonist: A drug wif an intermediate association and an intermediate dissociation, uh-hah-hah-hah.

In some receptor systems (e.g. acetywchowine at de neuromuscuwar junction in smoof muscwe), agonists are abwe to ewicit maximaw response at very wow wevews of receptor occupancy (<1%). Thus, dat system has spare receptors or a receptor reserve. This arrangement produces an economy of neurotransmitter production and rewease.[5]

Many genetic disorders invowve hereditary defects in receptor genes. Often, it is hard to determine wheder de receptor is nonfunctionaw or de hormone is produced at decreased wevew; dis gives rise to de "pseudo-hypo-" group of endocrine disorders, where dere appears to be a decreased hormonaw wevew whiwe in fact it is de receptor dat is not responding sufficientwy to de hormone.